Cases of progressive multifocal leukoencephalopathy with a long duration of disease have previously been reported but have hitherto received little attention. Renewed interest in this disease has occurred recently because of its association with monoclonal antibody treatments such as natalizumab and rituximab. We report a case that had a disease duration of 11 years, the second longest reported, in a patient not known to have had any form of immunosuppression. The patient’s earliest symptoms were of handwriting difficulties as a result of hand apraxias. The disease course was one of a slowly progressive, predominantly motor, neurodegenerative-like illness. Magnetic resonance imaging showed lesions early on in the disease course, the first time this has been shown in a long-standing case, but the diagnosis was made on post-mortem tissue. We review the literature on this topic and propose that progressive multifocal leukoencephalopathy should be considered in differential diagnoses even when the disease duration is many years long and also when there is no known form of immunosuppression.